This application describes a career development plan and research project designed to promote the transition of Dr. Morgane Thomsen from mentored fellow to an independent career in drug abuse research. Dr. Thomsen has acquired expertise in highly specialized behavioral techniques such as chronic intravenous drug self-administration in mice and rats, specializing in evaluating cocaine self- administration in mutant mice. The present proposal will develop and establish the candidate's mastery of additional procedures, specifically: manipulations of extinction in self-administration assays, and drug discrimination. During the 2-year mentored phase, the candidate plans to distinguish her research from her mentor's and establish a record of productivity in an original line of investigation. She will also gain experience and self-reliance in less technical areas (e.g., staff supervision, grants management) to prepare her for independence. The candidate plans to make muscarinic systems and their potential implications in drug addiction disorders her long-term focus as an academic researcher in behavioral pharmacology and genetics. Anticipated future directions include extending findings of the present proposal to models of polydrug abuse. The project will be conducted at the Alcohol and Drug Abuse Research Center at the McLean Hospital, Harvard Medical School. The institution generally, and the mentor S. Barak Caine and co-mentor Nancy Mello specifically, have extremely well-established records in drug abuse research, providing an ideal environment for fostering the careers of young researchers dedicated to this field. Dr. Thomsen's research project for this application proposes to evaluate the potential of drugs acting at specific muscarinic receptors to reduce abuse-related effects of cocaine. With the help of collaborators Professors P. Jeffery Conn and J|rgen Wess, Dr. Thomsen will combine novel, highly selective drugs with gene knockout technology to evaluate which muscarinic receptor subtypes mediate anti-cocaine effects of muscarinic agonists, and which mediate undesirable effects. First, a wide array of drugs will be tested in mice trained to discriminate cocaine from saline. Drugs that attenuate the discriminative stimulus of cocaine with little or no adverse effect (reduction in rates of behavior) will then be tested in mice and rats trained to self-administer cocaine chronically. With these latter assays, Dr. Thomsen will evaluate the ability of the drugs to selectively reduce cocaine self-administration (without decreasing food-maintained behavior) as acute and chronic treatment, and to facilitate extinction of a behavior associated with cocaine (in a strain of mice that show resistance to extinction). The ultimate goal of the project is to identify potential targets for treatment of cocaine addiction. PUBLIC HEALTH RELEVANCE: The focus of the five-year research plan as well as the lifelong career-objective of the young investigator is to develop new medications that target brain acetylcholine receptors. This is aimed principally at treating cocaine and amphetamine addictions, for which no effective medications currently exist, and secondly to improve upon existing dopamine-based medications with far fewer side-effects for disorders including Parkinson's Disease, Attention Deficit Hyperactivity Disorder, and Schizophrenia. Finally, because acetylcholine is known to modulate memory and cognition, it is highly likely that any breakthrough from this work would improve the lives of patients suffering from Alzheimer's Disease and other cognitive deficits.